3-(Benzoyl)-2-(4{40 -anilino carbonyl or benzoxy-alkyl piperazino)-propionitriles

ABSTRACT

The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R1 stands for a member selected from the group consisting of -CN, -CONH2, -COOH, -COONa and -COOK, R2 stands for a member selected from the group consisting of   X stands for alkylene having 1 to 4 carbon atoms, Y stands for a member selected from the group consisting of -OCO- and -CO-NH -, R3 and R4 stand for a member selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R5 stands for a member selected from the group consisting of hydrogen and -OH, the nucleus I may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents, THE NUCLEUS II may have 1 to 3 alkoxy, halogen or alkyl substituents, THE NUCLEUS III may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

llnite States atent Raabe et a1.

[451 Feb. 4, 11975 [54] 3-(BENZOYL)-2-(4-ANILINO CARBONYL 0R BENZOXY-ALKYL PIPERAZINO)- PROPIONITRILES [75] Inventors: Thomas Raabe, Heusenstamm Uber Offenbach, Germany; Adolf Stachel, deceased, late of Frankfurt (Main)-Fechenheim, Germany by lngeburg Lydia Katharina Stachel, heiress; Josef Scholtholt, Frankfurt (Main)-Fechenheim; Rolf-Eberhard Nitz, Bergen-Enkheim. both of Germany [73] Assignee: Cassella Farbwerke Mainkur Aktiengesellschaft, Frankfurt (Main)- Fechenheim, Germany [22] Filed: May 11, 1973 [21] Appl. No.: 359,442

Related US. Application Data [62] Division of Ser. No. 239,359, March 29, 1972.

[30] Foreign Application Priority Data Apr. 2, 1971 Germany 2116293 [52] US. Cl.. 260/268 CN, 260/465 E, 260/518 R, 260/518 A, 260/519, 260/558 A, 260/559 R,

424/250 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 CN [56] References Cited UNITED STATES PATENTS 3,594,384 7/1971 Stachel et al 260/268 CN 3,637,704 1/1972 Umemoto et a1. 260/268 R Primary ExaminerAlton D. Rollins Assistant Examiner-Jose Tovar Attorney, Agent, or Firm-Franics M. Crawford [57] ABSTRACT The present invention relates to new pharmacolog ically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula and their pharmaceutically acceptable acid addition salts, wherein R, stands for a member selected from the group consisting of --CN, -CONH -CO()H, C()()Na and (()()K,

R stands for a member selected from the group consisting of -N N x Y II and -1 t CH on ni l R R R X stands for alkylene having 1 to 4 carbon atoms,

Y stands for a member selected from the group consisting of OCO- and -CO-NH R and R stand for a member selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms,

R, stands for a member selected from the group consisting of hydrogen and OH,

the nucleus 1 may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents,

the nucleus 11 may have 1 to 3 alkoxy, halogen or alkyl substituents,

the nucleus 111 may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

6 Claims, No Drawings 3-(BENZOYL)-2-(4-ANILINO CARBONYL OR BENZOXY-ALKYL PIPERAZINO)- PROPIONITRILES wherein R, stands for CN, CON H COOH. COONa or COOK,

X Y R stands for -N N or -N CH CH I l l R R R X stands for alkylene having 1 to 4 carbon atoms,

Y stands for OCO or -CO-NH- R and R4 each stand for hydrogen or alkyl having up to 6 carbon atoms, and

R stands for hydrogen or OH,

the nucleus 1 may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents,

the nucleus ll may have 1 to 3 alkoxy, halogen or alkyl substituents, and

the nucleus Ill may be substituted by l to 3 methoxy groups.

The symbols R,, R R R4, R5, X and Y used in the above formula have the same meanings throughout the specification, and nuclei indexed I, ll or lll'may be substituted as defined above.

The compounds of general formula 1 contain at least one basic nitrogen atom and may consequently form or be formed as salts, in particular hydrohalides, and the invention extends to such acid addition salts, where pharmaceutically acceptable.

Preferred halogen substituents for the nucleus I and- /or the nucleus II are fluorine, chlorine and bromine. Preferred alkyl substituents of the nucleus 1 and of the nucleus ll contain 1 to 8 carbon atoms. Preferred alkoxy substuents are methoxy groups.

The compounds of formula I may be prepared, for

example, by the addition of amines of the general formula u H R to compounds of the general formula Those compounds of formula I in which R stands for I -N N x Y II and Y represents the OCO group, so that they have the general formula may also be synthesized by the addition of amines having the general formula to compounds of the general formula III followed by esterification of the adducts with benzoic acid derivatives of the general formula wherein Z stands for a halogen atom or the radical Those compounds of formula I in which R stands for a nitrile group may also be prepared by addition of HCN to vinylogous amines of the general formula ca N coon VIII x or, in some cases, by diazotation of the corresponding carbonamides X according to the following reaction equation:

X XI

wherein R is COONa or COOK, the carboxyl group in compound lX is converted to 'the corresponding sodium or potassium carboxylate.

Such of the starting materials III as are not yet described in the literature may be' prepared by known methods.

Thus. compounds of formula III, wherein R represents the nitrile group, may be prepared by a method analogous to that described by A.Nesmeyanov (Dokl.

XVI

XVIII Akad. Nauk SSSR, 115, page 315 (1957)), by reacting 20 lnitial compounds of formula III wherein R reprecompounds of the general formula XI -CO-CH=CH-Cl @wo-crwca-c a N with trimethylamine and subsequent reaction with KCN:

sents the CO-NH group may be prepared by partial saponification of the corresponding nitriles, for instance with concentrated sulfuric acid according to the following reaction scheme:

lnitial compounds of formula lll wherein R represents the COOH group may be prepared either by I N on @COCH=CH-Cl 3 3 @4o-cH=cH-N(cr1 3 XII XIII KCN @-co-ca=ca-u(cn 3 C0-CH=CH-CN XIII xIv The chlorides Xl necessary for this purpose may be prepared, as faras they are not yet described in litera- @-co-ca=cn-cona ture, according to known per se methods. The simplest method for the preparation of the chlorides Xl consists @-CO-CH=CH-CN (OH in the addition. in the presence of Friedel-Crafts-type diazotation of the corresponding carbonamides XX according to the following reaction scheme (mto -C0-CH=CH-COOH or directly by saponification of the nitriles XlX according to the following scheme @CO-CH=CHCOOH or by reaction of maleic acid anhydride with the correcatalysts. of suitable acid chlorides XV on acetylene 60 sponding benzene derivatives under the conditions of according to the following reaction equation:

xv XI In the case of certain acid chlorides this reaction is difficult to carry out, for instance if the nucleus l bears the. Friedel-Crafts reaction The compounds of general formula I of the present invention are valuable pharmaceuticals. They exert, es-

pecially where R, means CN, for instance, a distinct dilatory action on the cerebral vessels and are, in this respect. far superior to other known substances of this kind. The compounds of the present invention and their pharmaceutically acceptable salts may be employed together with pharmaceutically acceptable diluents or carriers for the preparation of pharmaceutical formulations such as tablets, dragees, suppositories, capsules, solutions, suspensions or emulsions.

These pharmaceutical preparations may also contain other therapeutically active substances.

Pharmacological investigations of the dilatory action of compounds according to the invention on the cerebral vessels were carried out in anaesthetized dogs by observing the changes in blood flow and oxygen tension of the brain-surface. The dogs were anaesthetized with Urethane-Chloralose-Dial-Nembutal (250--10-4 mg./kg. i.v.). Over the left-hand hemisphere of the brain the skull and the dura mater were opened by circular incision with a diameter of 2 to 3 cms. A heatconductive probe (Standard model P 1 of Messrs. Hartmann & Braun A.G., Frankfurt/Main) was applied to the brain under aslight pressure for local blood flow determinations in the cerebral cortex. (Literature consulted: K. GOLENHOFFEN, H. HENSEL, G. HILDE- BRANDT: Durchblutungsmessung mit Waermeleitelementen in Forschung und Klinik, Georg Thieme Verlag Stuttgart, 1963). Besides the heatconductive probe, 21 teflon-coated multiwire-platinum electrode supplied by Eschweiler of Kiel, was applied to the brain for measuring the local oxygen tension (Literature consulted: D.W. LUBBERS "Methods of measuring oxygen tensions of blood and organ surfaces in UP. PAYNE and D.W. HILL "Oxygen Measurements in Blood and Tissues and their Significance," .1. & A. Churchill Ltd., London 1966)). Blood pressure was measured in the femoral artery with the aid of an electromanometer of the STATHAM straingauge type.

The following table gives the results of the above pharmacological investigations.

Maximal change Maximal change in Maximal change of Preparation LD 50 Dosage of the cerebral oxygen tension of the blood pressure g./kg. mg./kg. blood flow the brain-surface (systolic/diastolic) mouse in in min. in in minutes in in minutes 3-( 3-methoxybenzoyl)-2' 1.0 50 +153 +32/+51 l5 (a-methyl-B-hydroxy-phenp.o. i.v.

ethylamino )-propionitrilc 5.0 +142 180 0/0 3-( 2'3 .4'-trimethoxy- +228 30 +47 3 +24l+25 13 benzoyl )-2-(a-methyl-B- 1.4 i.v.

hydroxy-phenethy1amino)- p.o. 100 +173 50 +200 50 +38/+26 l 8 propionitrile i.d.

3-(2,4,6-trimethoxy- 5.0 +271 15 +96 12 5/l4 8 benZOyU-Z-(a-methyI-B- 0.043 i.v.

hydroxy-phenethylamino)- i.v. 10.0 +44 25 +75 16 3/-14 7 propionitrile-hydrochloride i.d.

benzoy1)-2-(a-methyl-B- 5.0 121 38 +34 14 +18/+40 30 hydroxy-phenethylamino)- i.v.

propionitrile-hydrochloride 3(4'-chlorobenzoyl)-2- 3.0 +278 24 +25/+62 14 (a-methyl-B-hydroxy-pheni.v. i

ethylamino )-propionitri1c- 7.0 +133 18 0/0 hydrochloride i.d.

(fl-methyl-B-hydroxy-phen- 2.0 +205 19 +106 42 +1 27/+l 52 ethylamino)-propionitrilei.v.

hydrochloride (a-methyLB-hydroxy- 2.0 +90 14 11 10 +25/+50 17 phenethylamino)-propioi.v.

nitrile-hydrochloride trimethoxy-phcnethyl- '.v.

amino)-propionitrilchydrochloride 3-(2,3',4-lrimethoxy- 0.2 10.0 +212 56 +31 23 +3 1/+22 7 trimethoxyanilinol-carbonylmethyl-piperazinyl- 1.0 10.0 30 8 20 +2l/+5 20 (l)]-propionitrilep.o. i.d.

dihydrochloride 3-(2', 3', 4'-trimethoxydimethoxybenzy1)-pipei.v.

razinyl( 1 )]-propionitrile-dihydrochloride comparative substance: 10.0 0 0 0 0 0 O cinnarizine i.d.

7 The following examples are given for the purpose of a better understanding of the nature and the objects of this invention. The temperatures are given in degrees Centigrade.

EXAMPLE 1 2.87 p-chlorobenzoylacrylonitrile (formula: ClC H ,COCH=CHC=N) are dissolved in 30 c.c. dioxane, 2.27 g. norephedrin are added, the reaction mixture is completely dissolved with gentle heating and then allowed to stand for 48 hours at room temperature. Subsequently, it is concentrated in vacuo. The residue obtained is a dark colored oil which solidifies by the addition of petroleum ether. It is then sucked off, dried and triturated several times with warm water. The water-insoluble part is separated, dried, recrystallized once from benzene/petroleum ether and converted with ethanolic hydrochloric acid and with the concurrent use of anhydrous ether to the hydrochloride. The hydrochloride is reconverted in the usual manner to the base. After recrystallization from benzene/petroleum ether one obtains the 3-(pchlorobenzoyl)-2-(a-methyl-B-hydroxy-phenethylamino)-propionitrile having a melting point of Analysis: (C, H, Cl,N O

stirring at with '7 c.c. trimethylamine. While stirring, the solution is allowed to reach room temperature, then the reaction mixture is sucked off from the separated precipitate and washed with anhydrous acetone. The dry product is then suspended in c.c. benzene, a solution consisting of 3.8 g. trimethylammonium chloride in 4 c.c. water is added and a further solution consisting of 7 g. KCN in 36 c.c. water is added dropwise while cooling with ice and stirring. The reaction mixture is then heated to room temperature, stirred for another 15 hours. the benzene phase is separated and the aqueous phase is extracted twice with benzene. The combined benzene phases are washed once with water, dried with Na SO and concentrated in vacuo. By recrystallization of the muddy residue from ligroin one obtains the pchlorobenzoylacrylonitrile having a melting point of l44-l46.

Analysis: (C H Cl N O calculated: C 62.6; H 3.1; N 7.3.

found: C 63.0; H 3.5; N 7.2. Yield: 7.9 g. 59.4% of the theoretical Analogously to the description given hereinbefore it is possible to prepare, for instance, the following benzoylacrylonitriles:

@CO-CEFCH-CEN 2 3 4- (CH O) 0 K 2 4, 6- (CI-I 0) C H Melting Point Boiling Point:

calculated: C 66.6; H 5.6; N 8.2. found: C 66.3; H 5.5; N 8.0. Yield: 2.9 g. 56.5% of the theoretical The p-chlorobenzoylacrylonitrile required as starting material may be prepared as follows:

A solution consisting of 14 g. p-chlorobenzoylvinylchloride in 105 c.c. anhydrous acetone is admixed with 2-Br-C H Melting Point Boiling Point um -Continued -COCH=CHC1 I Meltlng POlHt Bolllng Polnt o 4CH C H 107-111 /2 mm.

o 4C H C H 112-118 /1 mm.

o 4--C I-1 C H 178-185 /1.5 mm.

o 2,4',5Cl C H 94 EXAMPLE 2 20 Melting point: 89-90 3.09 g. 2-[piperazinyl( 1 )]-acetic acid-3',4,5- Amflys's:

trimethoxyanilide are dissolved in 50 c.c. dioxane, 2.66 g. 2',3,4-trimethoxybenzoylacrylic acid are added and the mixture is stirred for 30 hours at 70. The separated precipitate is sucked off, washed first with dioxane, then thoroughly with water, dried and finally boiled with 75 c.c. alcohol. The residue thus obtained is the 3-[2,3,4-trimethoxybenzoyl]-2-[4-(3,4',S'- trimethoxyanilino)carbonylmethy1-pipera2iny1( 1 propionic acid.

Melting point: 169

Analysis: (C H N O calculated: C 58.4; H 6.4; N 7.3.

found: C 58.1; H 6.4; N 7.4.

Yield: 3 g. 52% of the theoretical The same product is obtained by treating N-[2- (2,3 ',4'-trimethoxybenzoyl )-1-cyanoethy1]-N '-(acet- 3,4,5-trimethoxy-anilido)-piperazine-hydrochloride (prepared by addition of 2-[piperazinyl( l )]-acetic acid-3,4,5 -trimethoxyanilide on 2,3,4-trimethoxybenzoylacrylonitrile analogously to the prescription of Example 5, melting point: 181) with concentrated sulfuric acid. The acid may be converted with an equimolar amount of sodium ethylate to its sodium salt.

Melting point: 250 dec.

The 2,3,4'-trimethoxybenzoylacrylic acid required as starting material may be prepared as follows:

4.5 g. 2',3,4'-trimethoxybenzoyl-acrylic acid amide are dissolved with stirring in 34 c.c. concentrated sulfuric acid. The mixture is cooled down to an internal temperature of -45, 3.55 g. NaNO are added and then 10 c.c. water are slowly added dropwise with stirring, whereby the temperature rises to --10. Subsequently, a further 51 c.c. water are added dropwise in such a manner that finally the temperature reaches +3 and stirring is continued for another 90 minutes at room temperature. The reaction mixture is then sucked off, the residue is washed with water. dissolved in soda solution of 10%, filtered off from a slightly turbid mass and the filtrate is acidified with hydrochloric acid of 10%. Obtained is an oily precipitate which solidifies after a short while. The reaction product is sucked off, washed with water and dried, then dissolved with gentle heating in toluene and filtered off from a minor residue. The filtrate is admixed with petroleum ether and the separated precipitate is sucked off. Obtained is the 2',3,4'- trimethoxybenzoylacrylic acid.

calculated: C 58.6; H 5.3; O 36.1. found: C 58.7; H 5.2; O 37.2. Yield: 3.3 g. 73% of the theoretical The 2-[piperazinyl( 1 )]-acetic acid-3',4',5 trimethoxy-anilide which is also required as starting material may be prepared as follows:

18.3 g. 3,4,5-trimethoxyaniline and 10.1 g. triethylamine are dissolved in 300 c.c. anhydrous dioxane. 1 1.3 g. chloroacetylchloride are added at 1520 with stirring and the reaction mixture is stirred for 16 hours at room temperature. It is then sucked off from the separated triethylammonium chloride. the filtrate is evaporated in vacuo. the residue is treated with ether and sucked off.

Obtained are 23 g. N-chloroacetyl-3,4',5- trimethoxyaniline having a melting point of 103.

A solution consisting of 27 g. piperazine in c.c. isopropanol is admixed, while stirring at room temperature, with a solution consisting of 14 g. N-chloroacetyl- 3,4,5-trimethoxyaniline in 60 c.c. dioxane. The reaction solution is then heated for 7 hours under reflux, evaporated and the residue is dissolved in 2N sodium hydroxide solution and chloroform. The chloroform phase is separated, the aqueous phase is again extracted with CHCl both chloroform extracts are combined, washed and concentrated in vacuo. The remaining oil solidifies by the addition of diis'opropylether. Obtained are after suction-filtration 15 g. 2- [piperaziny1(1)]-acetic acid-3,4,5-trimethoxyani1ide having a melting point of EXAMPLE 3 2 g. 3-methoxybenzoylacrylonitrile are dissolved in 30 c.c. dioxane, 1.39 g. N-hydroxyethylpiperazine are added and the solution is first allowed to stand for one hour at room temperature and then concentrated in vacuo. The residue is recrystallized from benzene/petroleum ether. Obtained are 3.2 g. N-[Z-(mmethoxybenzoyl)-1-cyano-ethyl]-N'-[hydroxyethyl]- piperazine having a melting point of 126128.

3.2 g. of the hydroxyethylpiperazine are dissolved in 40 c.c. dioxane, 1.03 g. triethylamine are added and, at room temperature, a solution consisting of 2.33 g. 3,4.- 5-trimethoxybenzoylchloride in 15 c.c. dioxane is added dropwise while stirring. Subsequently, the reaction mixture is stirred for another 16 hours at room temperature. A further 0.54 g. triethylamine as well as a solution consisting of 1.14 g. 3,4,5-trimethoxybenzoylchloride in dioxane are added and this mixture is again stirred for 16 hours at room temperature. After sucking off, the filtrate is concentrated in vacuo, the

. residue is dissolved in ethanolic hydrochloric acid and admixed with ether. The precipitate obtained is a slightly muddy hydrochloride. After conversion to the base and subsequent reconversion to the hydrochloride one obtains the N-[2-( m-methoxybenzoyl-l-cyanoethyl]-N 3 ,4, ,5 -trimethoxybenzoyloxyethyl piperazine-dihydrochloride in the form of crystals melting at 146.

Analysis: (C21H35Cl2N307) calculated: C 55.5; H 6.0; N 7.2.

found: C 55.0; H 6.1; N 7.1.

Yield: 2.9 g. 53% of the theoretical The 3'-methoxybenzoylacrylonitrile required as starting material may be prepared analogously to the description given in Example 1 from 3'-methoxybenzoylvinylchloride. The 3-methoxybenzoy1vinylchloride required for this purpose may be prepared as follows:

A solution consisting of 17.8 g. ethyl formiate and 30 g. 3-methoxyacetophenone is added dropwise, while stirring at 8- l, to a suspension of 13 g. sodium methylate in 100 c.c. anhydrous benzene. Stirring is continued for another 16 hours at room temperature, then the reaction mixture is sucked off, washed with anhydrous alcohol and the residue is dried in vacuo. Obtained are 38.9 g. of the sodium salt of the 3-methoxybenzoylvinyl alcohol.

24.2 g. of the sodium salt are suspended in 80 c.c. benzene. Subsequently, 100 c.c. water and 60 c.c. sulfuric acid of are added and the mixture is vigorously stirred. When it is completely dissolved, the benzene layer is separated and the aqueous phase is extracted twice with benzene.

The combined benzene extracts are then gently heated under reflux with 15.4 g. thionylchloride, the excess thionyl chloride and the benzene are then distilled off in vacuo and the residue is fractionated in vacuo.

Obtained is the 3'-methoxy-benzoylvinylchloride. Boiling point: 150/34 mm.

Analysis: (C,,,H,,ClO

calculated: C 61.0; H 4.5.

found: C 60.7; H 4.5.

Yield: 16.2 g. 38% of the theoretical Analogously, the following methoxylated benzoylvinylchlorides may be prepared from the corresponding acetophenones via the sodium salts of the benzoylvinylalcohols:

40H=CEFC1 G Melting point EXAMPLE 4 2 g. 2,3,4-trimethoxybenzoylacrylamide are dissolved in 40 c.c. dioxane, 1.14 g. norephedrin are added and the mixture is stirred for 20 hours at room temperature, then heated during one hour at and the solution is concentrated in vacuo. The remaining oil solidifies when it is treated with ether. The residue is sucked off, washed with ether, then dissolved in warmed ethyl acetate and the filtrate is admixed with petroleum ether whereby a precipitate is formed which crystallizes after a short while. It is sucked off and the residue is washed with petroleum ether.

Thus obtained is the N-[2-(2',3',4'- trimethoxybenzoyl l -carbonamido-ethyl norephedrin.

Melting point: Analysis: (CgzHggNgOg) calculated: C 63.5; H 6.7; N 6.7; O 23.1. found: C 63.4; H 7.1; N 6.4; O 23.5. Yield: 2.1 g. 67% of the theoretical The 2',3', 4-trimethoxybenzoylacrylic acid amide required as starting material may be prepared as follows:

8 g. 2',3,4-trimethoxybenzoylacrylonitril are dissolved in 40 c.c. concentrated sulfuric acid and heated -in a water bath to an internal temperature of 75. At

this temperature, the mixture is allowed to stand for 3 minutes, then cooled and poured onto about g. ice. The precipitated residue is sucked off and washed twice with little iced water. By recrystallization of the residue from water and with the concurrent use of little methanol one obtains the 2',3',4'-trimethoxybenzoylacrylic acid amide.

Melting point: l50-l52 Analysis: (C,,-,H,5NO5) calculated: C 58.9; H 5.7; N 5.3.

found: C 58.2; H 5.5; N 5.2.

Yield: 6.5 g. 76% of the theoretical EXAMPLE 5 Boiling point:

1se-171/1-2 mm.

1se -159/a mm.

trimethoxybenzoyl l -cyanoethyl ]-N acet-3 Q4 ,5 trimethoxyanilido )-piperazinehydrochloride.

Melting point: l78

Analysis: (C H CLN O calculated: C 56.7; H 6.2; Cl 6.0; N 9.4. found: C 56.8; H 6.4; Cl 5.8; N 9.6.

Analogously to the description given in Examples 1 5 the following compounds of the present invention N-[2-(3',4',5 10 may be obtained:

1 Q R R2 Melting point 0on O 2,3,4-(cr1 0) c r1 on -u N-C2H40-CO ocH 14o dihydro+ 3 chloride I 0on 0 2,3,4 (CH30)3C6H2 com! b1 u C2H40 c0 0on 187 hydro- OCH3 chlofiide 0 2,3,4 (CH3O)3C6H2 CN gCI-I 107 ocH 4 CH30C6H5 coon r1 N (CH o 00 Q ocH 221 O 3 CH3OC6H5 CN 5 (3H 92 CH3 OH 0 2,3,4 (CH30)3C6H2 CN 108 e21 OH c rr CN N-(|3H 101 o I 2,3,4(CH3O)3C6H2 CN -1-f n-cn -co-g 146 ocH I O 2,4,6(CH3O)3C6H2 on -NH- :H 1143 cu on Y 3 chlorlde -(ontinued R R Melting polnt 4 OCH 4 CH3C6H5 CN N NCH CO-g OCH3 183 hydro- H3 chloride 2,3,4-(ca o) c H CN -N N-cH CON 160 H hydro- 3 chloride 2,3,4(CH C H CN -N u-cn -co-n- 142 H hydro- Cl chloride 4-c1c H CN -N n-cn -co-n 133 H hydro- H C chloride What we claim is: 3 3. 3-(4-chloro-benzoyl)-2-[4'-(3",4",5"-

1. A compound of the formula trimethoxyanilino)-carbonyl-methyl-piperazinyl-( l propionitrile, or a pharmaceutically acceptable acid addition salt thereof.

4. 3-(4'-methyl-benzoyl)-2-[4'-(3",4,5- trimethoxyanilino)-carbonyl-methyl-piperazinyl-( l propionitrile. or a pharmaceutically acceptable acid addition salt thereof.

5. 3-(2',3,4'-trimethoxy-benzoyl)-2-[4'-(2",6"- dimethylanilino)-carhonyl-methyl-piperazinyl( l propionitrile, or a pharmaceutically acceptable acid addition salt thereof.

6. 3-(4-chloro-benzoyl)-2-[4-(2",6- dimethylanilino)-carbonyl-methyl-piperazinyl-( l )1- propionitrile, or a pharmaceutically acceptible acid addition salt thereof. 

1. A COMPOUND OF THE FORMULA
 2. 3-(2'',3'',4''-trimethoxy-benzoyl)-2-(4''-(3'''',4'''',5''''-trimethoxyanilino) -carbonylmethyl-piperazinyl-(1''))-propionitrile 1 or a pharmaceutically acceptable acid addition salt thereof.
 3. 3-(4''-chloro-benzoyl)-2-(4''-(3'''',4'''',5''''-trimethoxyanilino)-carbonyl-methyl -piperazinyl-(1''))-propionitrile, or a pharmaceutically acceptable acid addition salt thereof.
 4. 3-(4''-methyl-benzoyl)-2-(4''-(3'''',4'''',5''''-trimethoxyanilino)-carbonyl-methyl -piperazinyl-(1''))-propionitrile, or a pharmaceutically acceptable acid addition salt thereof.
 5. 3-(2'',3'',4''-trimethoxy-benzoyl)-2-(4''-(2'''',6''''-dimethylanilino)-carbonyl -methyl-piperazinyl-(1''))-propionitrile, or a pharmaceutically acceptable acid addition salt thereof.
 6. 3-(4''-chloro-benzoyl)-2-(4''-(2'''',6''''-dimethylanilino)-carbonyl-methyl -piperazinyl-(1''))-propionitrile, or a pharmaceutically acceptible acid addition salt thereof. 